DESCRIPTION (provided by investigator): Guillain-Barre Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) are autoimmune diseases characterized by inflammatory demyelinating lesions of the peripheral nervous system that cause devastating neurological deficits and paralysis. We have developed the first model of spontaneous autoimmune disease of the peripheral nervous system, called Spontaneous Autoimmune Peripheral Polyneuropathy (SAPP). NOD mice deficient in the co-stimulatory molecule B7-2 exhibit a progressive and generalized limb paralysis associated with severe demyelination and axonal damage due to massive inflammation of the peripheral nervous system. Adoptive transfer experiments showed that the disease is mediated, at least in part, by CD4+ T cells. The course of the disease and its pathophysiological features are strikingly similar to human GBS and CIDP. SAPP is observed in mice of the autoimmune-prone NOD background, which has been widely recognized as a valuable animal model of autoimmunity in humans. Furthermore, B7-2-deficient NOD mice do not develop diabetes. Thus, this animal model will provide insight into the influence of the co-stimulatory milieu on the polarization of autoimmunity towards different tissues and the development of distinct diseases in individuals presenting a general susceptibility to autoimmunity. The following specific aims are proposed to study this disease: Specific aim #1: To determine the antigen(s) targeted by autoreactive T cells in the peripheral nerves. Specific aim #2: To understand the influence of B7 costimulation on the polarization of autoimmunity in nod mice. Specific aim #3: To determine the immunopathology of SAPP, particularly the cell subsets and the effector mechanisms involved in the disease. Specific aim #4: To analyze the genetic control of SAPP. We propose to study the hypothesis that SAPP shares a subset of immunological and genetic attributes similar to those associated with the other autoimmune syndromes in the NOD strain. Our results will allow us to define genetic and immunological characteristics that determine the general susceptibility of individuals to autoimmunity and identify distinct mechanisms that lead to spontaneous destructive immune response in the nervous system versus the pancreas.